Background: Macrophages have a wide range of immunological and non-immunological functions, ranging from clearance of apoptotic cells, tissue remodelling, and release of pro and anti-inflammatory mediators at sites of tissue damage or infection. Subsets of phenoty- pically distinct macrophages may be uniquely adapted to perform these roles. Phenotypically and functionally distinguishable monocyte-de- rived cell lines also express unique metabolic profiles, suggesting that metabolism may have the potential to regulate function.

Methods: In order to determine whether differentiated macrophages display similar profound metabolic differences, and whether these differences affect function, we differentiated primary human blood monocytes under a range of oxygenation conditions and assessed their metabolic fingerprints using NMR spectroscopy. Results: Significant differences were seen in the metabolic profiles of M1 versus. M2 macrophages undergoing differentiation, with M1s displaying much reduced lactate levels, and corresponding increases in glucose, suggestive of gluconeogenesis via putative PFKFB3 (fructose- 1,6-bisphosphatase) activity. M1s were demonstrated to be constitu- tively active under oxygen reperfusion conditions, with no corre- sponding metabolic changes following LPS stimulation. M2s, in contrast, showed an expected hypoxia profile of increased lactate levels under differentiation, and remained inactive in reperfusion conditions. However, production of IL-10 following LPS stimulation was shown to be significantly reduced in hypoxic conditions.

Conclusion: A model of permissive inflammation during M1 infiltration under hypoxia may be suggested. In normal tissues reperfusion and reduced recruitment may therefore drive resolution aberrant recruitment of M1 macrophages or persitent tissue hypoxia may result in chronic inflammation such as that seen in the rheumatoid synovium.